P722: CHARACTERISATION OF PHF6 MUTATIONS IN MYELOID NEOPLASMS: THE MAYO CLINIC EXPERIENCE
Authors: Amrutha Sai Mittapalli, Bahga Katamesh, Muhamad Oum, Rong He, David Viswanatha, Patricia Greipp, Phuong Nguyen, Dragan Jevremovic, Cecilia Arana Yi, James M Foran, Kebede Benga, Naseema Gangat, Abhishek Mangaonkar, Antoine Saliba, Mrinal Patnaik, William J Hogan, Mark Litzow, Ayalew Tefferi, Mithun Shah, Hassan Alkhateeb, Aref Al-Kali
Journal: HemaSphere (2023)

Background: The PHD-finger protein 6 (PHF6) gene, on Xq26.3, functions as a tumor suppressor gene. The protein consists of 2 zinc finger protein domains (PHD1 and PHD2) that have a role in transcription regulation. PHF6 mutations (PHF6m) frequently occur in T-ALL but are only found in 3% of myeloid neoplasms (MN). The mutation is thought to be a late event in MN, but its significance is not well characterized. A better understanding of the prognostic value of PHF6m in MN can improve risk stratification. Aims: We hypothesize that PHF6m MN express unique clinical and genetic characteristics. Methods: We retrospectively analyzed 7935 patients with next-generation sequencing (NGS) between 2016-2022 at Mayo Clinic. PHF6m were identified in 116 patients and their clinical records were reviewed. Data was captured at the time of NGS. Overall Survival (OS) was measured using Kaplan Meyer estimates from date of NGS to death or last follow up. BlueSky Statistics V7.40 was used for data analysis. Results: 1) Characteristics: Of 116 patients, 87 were male (75%) and median age was 73 years (range, 27-92). Diagnosis included AML (n=38, 33%), MDS (n=32, 27%), MDS/MPN (n=23, 20%) and MPN (n=19, 9%). In MDS, excess blasts (EB) was the most common subtype (n=16, 53%). In the AML cohort, 12/38 patients (30%) had secondary AML (sAML). 17% of cases with PHF6m were therapy related MN (t-MN). Patients had a median white blood cell count, hemoglobin, and platelet count of 3.97x109/L, 9.6 x109/L and 57 x109/L, respectively. Abnormal cytogenetics were found in 51% of patients (21% had a complex karyotype). AML progression was seen in 10/76 non-AML cases (13%). Hematopoietic cell transplant (HCT) was done in 25 patients (22%). 2) PHF6m: Median VAF was 34% (range, 5-95%). There was no correlation between VAF and sex, diagnosis, blast count or mutation type. Mutations were nonsense (44%), frameshift (32%), splice-site (12%), and missense (11%). Mutations were mostly found in the extended PHD1 (ePHD1) (n=38,33%) and extended PHD2 (ePHD2) (n=52,45%) regions. Compared to ePHD1, mutations in ePHD2 were more significantly associated with SRSF2 co-mutations (31% vs 3%, p= <0.001) and less commonly with DNMT3A co-mutations (8% vs 26%, p= 0.02). The most common mutation type in ePHD1 was frameshift (53%), vs nonsense in ePHD2 (50%). Multiple PHF6m were found in 6 patients (5%) and isolated PHF6m in 10 (9%). 3) Co-Mutations: The median number of co-mutations was 3. The most common co-mutations were TET2 (43%), ASLX1 (37.1%), RUNX1 (29%) and SRSF2 (19%). In relation to diagnosis, median co-mutation frequency for AML, MDS, MDS/MPN, MPN and CCUS was 3,2,3,3 and 1.55 (p= 0.003). 4) Survival: Median overall survival (mOS) was 22 months (median follow up of 27.5 months). HCT led to longer OS (not reached vs 18 months, p =.04). Patients with ePHD1 mutations had lower mOS than those with ePHD2 mutations (11 vs 43 months, p=.009). Survival worsened with increasing number of co-mutations (HR =1.33, p =0.003). On multi-variant analysis, HCT (HR=0.5, p=0.046), number of co-mutations (HR= 1.33, p=0.003) and mutation in ePHD1 vs ePHD2 (HR=2.2, p=0.01) retained statistical significance. Survival did not vary with diagnosis, MDS subtype, blast count or mutation type. Summary/Conclusion In our cohort, PHF6m were more common in males. While PHF6m were more common in AML and MDS, they were seen in other subtypes of MN as well. They carried multiple co-mutations, TET2m being the most common. Most (78%) mutations were in ePHD1 and ePHD2 regions of the gene. HCT had a favorable impact on PHF6m MN, while ePHD1 mutations were associated with lower mOS.Keywords: Myeloid malignancies, Survival, Gene mutation